Cholecystokinin is structurally and functionally related to gastrin. The active C-terminal tetrapeptide amide of gastrin is duplicated in cholecystokinin. The major structural difference that dictates whether a peptide of the CCK-gastrin family has a gastrin-like or CCK-like pattern of activity is the position of the tyrosyl residue and whether or not it is sulfated. Gastrointestinal Hormones, edited by George B. Jerzy, Glass Raven Press, New York, 1980, pp. 512-513. CCK is a polypeptide which was originally isolated from the gut. Later investigations, however, discovered CCK is also localized in the mammalian central nervous system; particularly high levels of the octapeptide form (CCK-8) are found in hippocampus. Immunocytochemical staining has revealed that CCK-8 containing neurons appear to be interneurons in the hippocampus. "Inhibition of Synaptic Transmission in the Hippocampus by Cholecystokinin (CCK) and its Antagonism by a CCK Analog (CCK.sub.27-33)" (Elsevier, B. A. MacVicar, J. P. Kerrin, and J. S. Davison, Basic Research 406:130-135, 1987).
Agents acting at central cholecystokinin (CCK) receptors may induce satiety (Schick, Yaksh, and Go, Regulatory Peptides 14:277-291, 1986). They are also expected to act as analgesics (Hill, Hughesm and Pittaway, Neuropharmacology 26:289-300, 1987), and as anticonvulsants (MacVicar, Kerrin, and Davison, Brain Research 406:130-135, 1987).
Reduced levels of CCK-peptides have been found in the brains of schizophrenic patients compared with controls (Roberts, et al., Brain Research 288:199-211, 1983). It has been proposed that changes in the activity of CCK neurones projecting to the nucleus accumbens may play a role in schizophrenic processes by influencing dopaminergic function (Totterdell and Smith, Neuroscience 19:181-192, 1986). This is consistent with numerous reports that CCK peptides modulate dopaminergic function in the basal ganglia and particularly the nucleus accumbens (Weiss, Tanzer, and Ettenberg, Pharmacology, Biochemistry and Behaviour 30:309-317, 1988; Schneider, Allpert, and Iversen, Peptides 4:749-753, 1983). It may therefore be expected that agents modifying CCK receptor activity may have therapeutic value in conditions associated with disturbed function of central dopaminergic function such as schizophrenia and Parkinson's disease.
CCK and gastrin peptides share a common carboxy terminal pentapeptide sequence, and CCK peptides can bind to the gastrin receptor of the stomach mucosa and elicit acid secretion in many species including human (Kontruek, Gastrointestinal Hormones, Ch. 23:529-564, 1980, ed. G. B. J. Glass, Raven Press, N.Y.). The receptors for CCK have been classified into two subtypes according to their affinity for CCK fragments and their analogs. CCK-A receptors are found predominantly in peripheral tissues such as pancreas and gall bladder. They have high affinity for the sulfated octapeptide (CCK-8S) and lower affinity for the corresponding desulfated fragment CCK-8d, CCK-4 and gastrin. Conversely, CCK-B receptors are widely distributed throughout the brain and exhibit high affinity for CCK-8s, CCK-4 and gastrin. (Innis, R. B.; Synder, S. H., Proc. Natl. Acad. Sci. USA, 77:6917-6921, 1980 and Moran, T. H., et al., Brain Research, 362:175-179, 1989). Antagonists of the CCK-B receptor would also be expected to be antagonists at the stomach gastrin receptor, and this would also be of value for conditions involving excessive acid secretion.
CCK and gastrin peptides have trophic effects on the pancreas and various tissues of the gastrointestinal tract (Johnson, Gastrointestinal Hormones, edited by George B. Jerzy Glass, "Effect of Gastrointestinal Hormones on Growth of Gastrointestinal Tissue," Chapter 22:507-527), actions which are associated with increased DNA and RNA synthesis. Moreover, gastrin secreting cells are associated with certain gastrointestinal tumors as in the Zollinger-Ellison syndrome (Stadil, Gastrointestinal Hormones, edited by George B. Jerzy Glass, "Gastrinomas," Chapter 30:729-739), and some colorectal tumors may also be gastrin/CCK dependent (Singh, et al., Cancer Research 46:1612, 1986; Smith, J. P., Gastroenterology 95:1541, 1988). Antagonists of CCK/gastrin receptors could therefore be of therapeutic value as antitumor agents.
The CCK peptides are widely distributed in various organs of the body including the gastrointestinal tract, endocrine glands, and the nerves of the peripheral and central nervous systems. Various biologically active forms have been identified including a 33-amino acid hormone and various carboxylterminus fragments of this peptide (e.g., the octapeptide CCK.sub.26-33 and the tetrapeptide CCK.sub.30-33). (G. J. Dockray, Br. Med. Bull. 38(3):253-258, 1982).
The various CCK peptides are thought to be involved in the control of smooth muscle contractility, exocrine and endocrine gland secretion, sensory nerve transmission, and numerous brain functions. Administration of the native peptides cause gall bladder contraction, amylase secretion, excitation of central neurons, inhibition of feeding, anticonvulsive actions and other behavioral effects. (Cholecystokinin: Isolation, Structure and Functions, G. B. J. Glass, ed., Raven Press, New York, 1980, pp. 169-221; J. E. Morley, Life Sciences 27:355-368, 1980; Cholecystokinin in the Nervous System, J. de Belleroche and G. J. Dockray, ed., Ellis Horwood, Chichester, England, 1984, pp. 110-127).
The high concentrations of CCK peptides in many brain areas also indicate major brain functions for these peptides (G. J. Dockray, Br. Med. Bull. 38(3):253-258, 1982). The most abundant form of brain CCK found is CCK.sub.26-33, although small quantities of CCK.sub.30-33 exist (Rehfeld and Gotterman, J. Neurochem. 32:1339-1341, 1979). The role of central nervous system CCK is not known with certainty, but it has been implicated in the control of feeding (Della-fera and Baile, Science 206:471-473, 1979).
Currently available appetite suppressant drugs either act peripherally, by increasing energy expenditure (such as thyroxine), or in some other manner (such as the biguanides), or act by exerting a central effect on appetite or satiety.
Centrally acting appetite suppressants either potentiate central catecholamine pathways and tend to be stimulants (for example, amphetamine), or influence serotonergic pathways (for example, fenfluramine). Other forms of drug therapy include bulking agents which act by filling the stomach, thereby inducing a "feeling" of satiety.
CCK is known to be present in some cortical interneurones which also contain gamma-aminobutyric acid (GABA) (H. Demeulemeester, et al., J. Neuroscience 8:988-1000, 1988). Agents that modify GABA action may have utility as anxiolytic or hypnotic agents ((S. C. Harvey, The Pharmacological Basis of Therapeutics (7th ed.) 1985, pp. 339-371, MacMillan)). Thus, agents which modify CCK action may have parallel anxiolytic or hypnotic activities. The role of CCK in anxiety is disclosed in TIPS 11:271-273, 1990, and is fully detailed in Woodruff, G.N. and Hughes, J., 1991, Ann. Rev. Pharmacol. and Toxicol. 31, 469-501.
Since the identification in brain extracts of the carboxyl (C)-terminal octapeptide of CCK-8, much evidence has arisen to suggest that CCK-related peptides have neuroregulatory roles in the central nervous system (CNS) in addition to their well-known hormonal functions in controlling digestion. The Physiology of Cholecystokinin in Brain and Gut, British Medical Bulletin, 38(3):353-358, 1982, by G. J. Dockray.
It is an object of the present invention to described pharmaceutical compositions that are effective to suppress the appetite in a mammal.
It is another object of the present invention to describe compositions that are effective to reduce gastric acid secretion in a mammal.
It is yet another object of the present invention to describe compositions useful to effect a reduction of anxiety in a mammal.
It is still another object of the present invention to describe compositions useful to effectively treat gastrointestinal ulcers in a mammal.
It is another object of the present invention to describe compositions useful to effectively treat psychotic behavior in a mammal.
Still further, it is an object of the present invention to describe compositions useful to effectively block the reaction caused by withdrawal from drug or alcohol use in a mammal.
It is still a further object of the present invention to describe compositions useful to effectively potentiate the affects of morphine and other opioids in treating pain in a mammal.
It is yet another object of the present invention to describe compositions useful to effectively treat and/or prevent panic in a mammal.
It is an object of the present invention to describe compositions which can be radio labeled and are useful for effecting diagnosis of gastrine-dependent tumors in a mammal.
It is a further object of the present invention to produce a key intermediate in the present invention by reacting the 2-hydrazine quinazoline derivative with hydrogen to obtain the 2-amino quinazoline derivative.